Jones T R, Smithers M J, Taylor M A, Jackman A L, Calvert A H, Harland S J, Harrap K R
J Med Chem. 1986 Apr;29(4):468-72. doi: 10.1021/jm00154a007.
Four new analogues of the antifolate N10-propargyl-5,8-dideazafolic acid were prepared that were substituted in the benzoyl ring. The 2'-chloro and 2'-methyl analogues were prepared from the appropriately substituted p-nitrobenzoic acids. The route to the 3'-chloro and 3',5'-dichloro analogues was by chlorination of diethyl N10-propargyl-5,8-dideazafolate and diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate, respectively, using sulfuryl chloride. The compounds were tested for their inhibition of purified L1210 thymidylate synthase (TS), for their inhibition of purified L1210 dihydrofolate reductase (DHFR), and for their inhibition of the growth of L1210 cells in culture. The 2'-chloro substituent reduced the TS inhibition by twofold and the 2'-methyl substituent reduced it by 20-fold; the 3'-chloro and 3',5'-dichloro derivatives were very poor inhibitors. The substituents only slightly affected the DHFR inhibition. None of the compounds improved upon N10-propargyl-5,8-dideazafolic acid in inhibiting the growth of L1210 cells in culture.
制备了四种抗叶酸剂N10-炔丙基-5,8-二氮杂叶酸的新类似物，它们在苯甲酰环上有取代基。2'-氯和2'-甲基类似物由适当取代的对硝基苯甲酸制备。3'-氯和3',5'-二氯类似物的合成路线分别是通过用硫酰氯氯化N10-炔丙基-5,8-二氮杂叶酸二乙酯和N-[4-(丙-2-炔基氨基)苯甲酰基]-L-谷氨酸二乙酯。测试了这些化合物对纯化的L1210胸苷酸合成酶（TS）的抑制作用、对纯化的L1210二氢叶酸还原酶（DHFR）的抑制作用以及对培养的L1210细胞生长的抑制作用。2'-氯取代基使TS抑制作用降低了两倍，2'-甲基取代基使其降低了20倍；3'-氯和3',5'-二氯衍生物是非常差的抑制剂。这些取代基对DHFR抑制作用的影响很小。在抑制培养的L1210细胞生长方面，没有一种化合物比N10-炔丙基-5,8-二氮杂叶酸表现更好。
